scholarly journals Validation of genome-wide polygenic risk scores for coronary artery disease in French Canadians

2019 ◽  
Author(s):  
Florian Wünnemann ◽  
Ken Sin Lo ◽  
Alexandra Langford-Avelar ◽  
David Busseuil ◽  
Marie-Pierre Dubé ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Scores ◽  
French Canadian ◽  
French Canadians ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Artery Disease ◽  
The Impact ◽  
Cad Risk

AbstractCoronary artery disease (CAD) represents one of the leading causes of morbidity and mortality worldwide. Given the healthcare risks and societal impacts associated with CAD, their clinical management would benefit from improved prevention and prediction tools. Polygenic risk scores (PRS) based on an individual’s genome sequence are emerging as potentially powerful biomarkers to predict the risk to develop CAD. Two recently derived genome-wide PRS have shown high specificity and sensitivity to identify CAD cases in European-ancestry participants from the UK Biobank. However, validation of the PRS predictive power and transferability in other populations is now required to support their clinical utility. We calculated both PRS (GPSCAD and metaGRSCAD) in French-Canadian individuals from three cohorts totaling 3639 prevalent CAD cases and 7382 controls, and tested their power to predict prevalent, incident and recurrent CAD. We also estimated the impact of the founder French-Canadian familial hypercholesterolemia deletion (LDLR delta > 15kb deletion) on CAD risk in one of these cohorts and used this estimate to calibrate the impact of the PRS. Our results confirm the ability of both PRS to predict prevalent CAD comparable to the original reports (area under the curve (AUC) = 0.72-0.84). Furthermore, the PRS identified about 6-7% of individuals at CAD risk similar to carriers of the LDLR delta > 15kb mutation, consistent with previous estimates. However, the PRS did not perform as well in predicting incident (AUC= 0.56 - 0.60) or recurrent (AUC= 0.56 - 0.60) CAD. This result suggests that additional work is warranted to better understand how ascertainment biases and study design impact PRS for CAD. Collectively, our results confirm that novel, genome-wide PRS are able to predict CAD in French-Canadians; with further improvements, this is likely to pave the way towards more targeted strategies to predict and prevent CAD-related adverse events.

scholarly journals Validation of Genome-Wide Polygenic Risk Scores for Coronary Artery Disease in French Canadians

2019 ◽  
Vol 12 (6) ◽  
Author(s):  
Florian Wünnemann ◽  
Ken Sin Lo ◽  
Alexandra Langford-Avelar ◽  
David Busseuil ◽  
Marie-Pierre Dubé ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Scores ◽  
French Canadians ◽  
Polygenic Risk ◽  
Genome Wide ◽  
Artery Disease

scholarly journals Polygenic Hyperlipidemias and Coronary Artery Disease Risk

2019 ◽  
Author(s):  
Pietari Ripatti ◽  
Joel T Rämö ◽  
Nina J Mars ◽  
Sanni Söderlund ◽  
Christian Benner ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Cumulative Exposure ◽  
Risk Scores ◽  
Lipid Levels ◽  
Artery Disease ◽  
The Impact ◽  
Cad Risk

AbstractBackgroundHyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). Monogenic familial hypercholesterolemia associates with higher increase in CAD risk than expected from a single LDL-C measurement, likely due to lifelong cumulative exposure to high LDL-C. It remains unclear to what extent a high polygenic load of LDL-C or TG-increasing variants associates with increased CAD risk.Methods and ResultsWe derived polygenic risk scores (PRS) with ∼6M variants for LDL-C and TG with weights from a UK biobank-based genome-wide association study with ∼500K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the FINRISK cohort, and to CAD risk in 135 300 individuals (13 695 CAD cases) from the FinnGen project.In FINRISK, LDL-C ranged from 2.83 (95% CI 2.79-2.89) to 3.80 (3.72-3.88) and TG from 0.99 (0.95-1.01) to 1.52 (1.48-1.58) mmol/l between the lowest and highest 5% of the respective PRS distributions. The corresponding CAD prevalences ranged from 8.2% to 12.7% for the LDL-C PRS and from 8.2% to 12.1% for the TG PRS in FinnGen. Furthermore, CAD risk was 1.36-fold higher (OR, 95% CI 1.24-1.49) for the LDL-C PRS and 1.31-fold higher (1.20-1.44) for the TG PRS for those with the PRS >95th percentile vs those without. These estimates were only slightly attenuated when adjusting for a CAD PRS (OR 1.26 [95% CI 1.15-1.39] for LDL-C and 1.21 [1.10-1.32] for TG PRS).ConclusionsThe CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and mostly independent of a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing more direct guidance for clinical translation.

scholarly journals Polygenic Hyperlipidemias and Coronary Artery Disease Risk

2020 ◽  
Vol 13 (2) ◽  
Author(s):  
Pietari Ripatti ◽  
Joel T. Rämö ◽  
Nina J. Mars ◽  
Yu Fu ◽  
Jake Lin ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Odds Ratio ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Risk Scores ◽  
Lipid Levels ◽  
Artery Disease ◽  
The Impact ◽  
Cad Risk

Background: Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk. Methods: We derived polygenic risk scores (PRSs) with ≈6M variants separately for LDL-C and TG with weights from a UK Biobank–based genome-wide association study with ≈324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen). Results: In FINRISK, median LDL-C was 3.39 (95% CI, 3.38–3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82–2.94) to 3.78 (95% CI, 3.71–3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18–1.20) mmol/L, ranging from 0.97 (95% CI, 0.94–1.00) to 1.55 (95% CI, 1.48–1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24–1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19–1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16–1.38] for LDL-C and 1.24 [95% CI, 1.13–1.36] for TG PRS). Conclusions: The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.

scholarly journals Broad Clinical Manifestations of Polygenic Risk for Coronary Artery Disease in the Women′s Health Initiative

2021 ◽  
Author(s):  
Shoa L. Clarke ◽  
Matthew Parham ◽  
Aladdin H. Shadyab ◽  
Simin Liu ◽  
Charles Kooperberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Clinical Manifestations ◽  
Polygenic Risk ◽  
Health Initiative ◽  
Genome Wide ◽  
Artery Disease ◽  
Clinical Measurements ◽  
Cad Risk

Background: The genetic basis for coronary artery disease (CAD) risk is highly complex. Genome-wide polygenic risk scores (PRS) can help to quantify that risk, but the broader impacts of polygenic risk for CAD are not well characterized. Methods: We measured polygenic risk for CAD using the metaGRS, a previously validated genome-wide PRS, in a subset of genotyped participants from the Women′s Health Initiative (WHI) and applied a phenome-wide association study framework to assess associations between the PRS and broad range of blood biomarkers, clinical measurements, and outcomes. Results: Polygenic risk for CAD was associated with a variety of biomarkers, clinical measurements, behaviors, and diagnoses related to traditional risk factors, as well as risk-enhancing factors such as elevated lipoprotein(a), increased central adiposity, earlier age of menopause, and rheumatoid arthritis. Analysis of adjudicated outcomes showed a graded association between atherosclerosis related outcomes, with the highest odds ratios being observed for the most severe manifestations of CAD. Higher polygenic risk for CAD was also associated with decreased risk for any incident cancer, breast cancer, and invasive breast cancer but a younger age of death. Conclusion: Polygenic risk for CAD has broad clinical manifestations, reflected in biomarkers, clinical measurements, behaviors, and diagnoses. Some of these associations may represent direct pathways between genetic risk and CAD while others may reflect pleiotropic effects independent of CAD risk.

scholarly journals Polygenic risk scores for coronary artery disease and subsequent event risk amongst established cases

2020 ◽  
Vol 29 (8) ◽  
pp. 1388-1395
Author(s):  
Laurence J Howe ◽  
Frank Dudbridge ◽  
Amand F Schmidt ◽  
Chris Finan ◽  
Spiros Denaxas ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Scores ◽  
Effect Estimate ◽  
Inverse Association ◽  
Uk Biobank ◽  
Case Control Studies ◽  
Polygenic Risk ◽  
Increased Risk ◽  
Artery Disease

Abstract Background There is growing evidence that polygenic risk scores (PRSs) can identify individuals with elevated lifetime risk of coronary artery disease (CAD). Whether they can also be used to stratify the risk of subsequent events among those surviving a first CAD event remain uncertain, with possible biological differences between CAD onset and progression, and the potential for index event bias. Methods Using two baseline subsamples of UK Biobank: prevalent CAD cases (N = 10 287) and individuals without CAD (N = 393 108), we evaluated associations between a CAD PRS and incident cardiovascular and fatal outcomes. Results A 1 SD higher PRS was associated with an increased risk of incident myocardial infarction (MI) in participants without CAD (OR 1.33; 95% CI 1.29, 1.38), but the effect estimate was markedly attenuated in those with prevalent CAD (OR 1.15; 95% CI 1.06, 1.25) and heterogeneity P = 0.0012. Additionally, among prevalent CAD cases, we found an evidence of an inverse association between the CAD PRS and risk of all-cause death (OR 0.91; 95% CI 0.85, 0.98) compared with those without CAD (OR 1.01; 95% CI 0.99, 1.03) and heterogeneity P = 0.0041. A similar inverse association was found for ischaemic stroke [prevalent CAD (OR 0.78; 95% CI 0.67, 0.90); without CAD (OR 1.09; 95% CI 1.04, 1.15), heterogeneity P < 0.001]. Conclusions Bias induced by case stratification and survival into UK Biobank may distort the associations of PRS derived from case-control studies or populations initially free of disease. Differentiating between effects of possible biases and genuine biological heterogeneity is a major challenge in disease progression research.

Polygenic Risk Scores in Coronary Artery Disease and Atrial Fibrillation

2020 ◽  
Vol 29 (4) ◽  
pp. 634-640 ◽  
Author(s):  
Patrick A. Gladding ◽  
Malcolm Legget ◽  
Diane Fatkin ◽  
Peter Larsen ◽  
Robert Doughty
Keyword(s):  
Atrial Fibrillation ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Risk Scores ◽  
Polygenic Risk ◽  
Artery Disease

scholarly journals Unique and Varied Contributions of Traditional CVD Risk Factors: A Systematic Literature Review of CAD Risk Factors in China

2013 ◽  
Vol 7 ◽  
pp. CMC.S10225 ◽  
Author(s):  
Joanne Foody ◽  
Yong Huo ◽  
Linong Ji ◽  
Dong Zhao ◽  
Dylan Boyd ◽  
...  
Keyword(s):  
Risk Factors ◽  
Systematic Review ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Real World ◽  
Odds Ratio ◽  
Lipid Levels ◽  
Artery Disease ◽  
The Impact ◽  
Cad Risk

This study is the first systematic review of risk factors for stroke in China and supports the importance of current public health initiatives to manage the risk factors appropriately to reduce risk of stroke in high risk patients. Additionally, this study has been co-authored by prominent Chinese and US physicians and researchers with expertise in cardiovascular disease, neurologic disorders, epidemiology, and real world data. While there have been several systematic reviews of real world associations of risk factors for coronary artery disease, none focus specifically on the population of China, where there is growing evidence that such risk factors are poorly treated or uncontrolled, especially in rural areas. Background To better understand the impact of traditional cardiovascular risk factors on risk of coronary artery disease (CAD) in China, a systematic review of all Chinese observational studies published in either English or Chinese in MEDLINE and EMBASE over the last 5 years was performed and the association between any of 5 traditional risk factors (ie, hypertension, diabetes, elevated lipid levels, obesity, and smoking) and the risk of CAD was studied. Methods and Results The study found a consistent relationship between lipid levels and CAD. Higher low-density lipoprotein cholesterol values were associated with greater risk of CAD, with an odds ratio as high as 3.31. Other factors found to be significant contributors to the risk of CAD included hypertension (crude odds ratio range of 1.40-5.11), diabetes (1.50-5.97), and smoking (1.37-5.19). An association between obesity and CAD in China was observed, but the evidence supporting this was considered weak due to the paucity of studies found as part of this review. Conclusions This review provides a systematic summary of CAD risk factors in China and demonstrates the important differences that exist in CAD risk factors between countries and regions. Approaches to reduce CAD globally must take into account the unique risk factors that drive CAD in each country and region as is demonstrated by these findings.

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